Respiratory Syncytial Virus (RSV) is a leading cause of serious respiratory disease in young children and the elderly worldwide and there is no vaccine available against this pathogen. Human respiratory syncytial virus (HRSV) infection commonly results in bronchiolitis and is the leading cause for infant hospitalization in the developed countries. In addition, HRSV is increasingly being described as a major pathogen in the elderly, transplant patients, and chronic obstructive pulmonary disease (COPD) patients (ref 1). The development of a safe and immunogenic vaccine to address the infant and elderly population presents a unique opportunity.
Previous methods of viral inactivation for vaccine formulation, such as formaldehyde, resulted in enhanced pulmonary disease and mortality. Extensive research into the development of viral vaccines to address HRSV has met with limited success. Some of the major challenges for HRSV vaccine development include early age of infection, evasion of innate immunity, failure of natural infection to induce immunity that prevent infection, and the demonstration of vaccine-enhance illness (ref 2).
Approaches have included inactivation of viruses with formalin and the demonstration of vaccine-induced enhancement of diseases when infected with HRSV. The observation that formalin inactivated vaccines have shown disease-enhancement, including showing the skewed immune response that is important to prevent enhancement, and priming by mature dendritic cells, are essential for a protective immune response. Moreover, having F protein in its native state to maintain conformational epitopes is essential for the generation of neutralizing antibodies (refs. 3, 4, 5). The uses of live attenuated vaccines have met with limited success, as the vaccines have been shown to be minimally immunogenic (ref 6). The utilization of a recombinant F protein vaccine showed reduced immunogenicity, with the demonstration that the purified F protein is structurally immature and not the appropriate version for eliciting neutralizing antibodies (ref 7, 8). With the use of a subunit vaccine, having an optimal level of F protein is critical for inducing the appropriate immune response, as the subunit vaccines have been hindered by the inefficient and inappropriate expression of F protein (ref 9. 10). The observation that a subunit vaccine containing F protein, even with adjuvant, is not completely protective and optimal (ref 11), suggests that F protein presentation within its native state in the virion is essential for usage as a vaccine.
The biological challenges and safety concerns of development of a HRSV-L19 present a unique opportunity for a safe and durable vaccine against HRSV.
As with most vaccines, greater immunogenicity is also sought as it correlates with greater efficacy in humans. The prior art has typically disclosed the use of recombinant proteins (e.g., U.S. Pat. Nos. 7,192,595; 6,194,546; 5,962,298), as well as the addition of adjuvants such as aluminum (U.S. Pat. No. 6,861,244) and muramyldipeptide (U.S. Pat. No. 4,826,687) to compositions to increase the immunogenicity. However, there still exists a need to develop highly effective RSV vaccines with improved storage stability and ease of administration, which are characteristics of the nanoemulsion vaccines of the present invention.
Prior teachings related to nanoemulsions are described in U.S. Pat. No. 6,015,832, which is directed to methods of inactivating Gram-positive bacteria, a bacterial spore, or Gram-negative bacteria. The methods comprise contacting the Gram-positive bacteria, bacterial spore, or Gram-negative bacteria with a bacteria-inactivating (or bacterial-spore inactivating) emulsion. U.S. Pat. No. 6,506,803 is directed to methods of killing or neutralizing microbial agents (e.g., bacterial, virus, spores, fungus, on or in humans using an emulsion. U.S. Pat. No. 6,559,189 is directed to methods for decontaminating a sample (human, animal, food, medical device, etc.) comprising contacting the sample with a nanoemulsion. The nanoemulsion, when contacted with bacteria, virus, fungi, protozoa or spores, kills or disables the pathogens. The antimicrobial nanoemulsion comprises a quaternary ammonium compound, one of ethanol/glycerol/PEG, and a surfactant. U.S. Pat. No. 6,635,676 is directed to two different compositions and methods of decontaminating samples by treating a sample with either of the compositions. Composition 1 comprises an emulsion that is antimicrobial against bacteria, virus, fungi, protozoa, and spores. The emulsions comprise an oil and a quaternary ammonium compound. U.S. Pat. No. 7,314,624 is directed to methods of inducing an immune response to an immunogen comprising treating a subject via a mucosal surface with a combination of an immunogen and a nanoemulsion. The nanoemulsion comprises oil, ethanol, a surfactant, a quaternary ammonium compound, and distilled water. US-2005-0208083-A1 and US-2006-0251684-A1 are directed to nanoemulsions having droplets with preferred sizes. US-2007-0054834-A1 is directed to compositions comprising quaternary ammonium halides and methods of using the same to treat infectious conditions. The quaternary ammonium compound may be provided as part of an emulsion. Finally, US-2007-0036831-A1 is directed to nanoemulsions comprising an anti-inflammatory agent. However, none of these references teach the methods, compositions and kits of the present invention.
In particular, U.S. Pat. No. 7,314,624 describes nanoemulsion vaccines. However, this reference does not teach the ability to induce a protective immune response to RSV using the immunogen of the invention.
There remains a need in the art for an effective RSV vaccine and methods of making and using the same. The present invention satisfies these needs.